Task-induced 1/f slope modulation as a paradigm-independent marker of cognitive control in multiple sclerosis

Multiple sclerosis (MS) is a chronic neuro-degenerative and inflammatory disease causing motor, sensory, and cognitive deficits, including impairments in working memory and attention. These cognitive deficits may arise from an imbalance between excitatory and inhibitory neural activity due to synaptic loss. Recent studies suggest that the aperiodic 1/f slope, a neural marker reflecting excitation/inhibition (E/I) balance, could serve as a biomarker for cognitive control. This study examines 1/f slope modulation during cognitive tasks in people with MS and healthy controls to investigate its potential as a paradigm-independent marker of cognitive control.

We analyzed the Magnetoencephalography (MEG) data collected from 126 participants: 44 healthy controls (HCs), 61 people with MS not treated with benzodiazepines (pwMS(BZDn)), and 21 pwMS treated with benzodiazepines (pwMS(BZDp)). Participants performed an auditory oddball task and a visual-verbal n-back working memory task. After preprocessing MEG data, we used the FOOOF algorithm to extract the aperiodic 1/f slope from power spectral densities across 42 cortical parcels.

Through this analysis, we observed significant increases in the 1/f slope following stimulus onset for all stimulus types, with more pronounced modulation for non-standard stimuli (targets and distractors), especially within the temporal cortex. Group comparisons revealed less slope modulation in pwMS(BZDp) compared to HCs during distractor stimuli, indicating impaired inhibitory control linked to benzodiazepine treatment. Positive correlations of 1/f slope modulation across auditory oddball and n-back tasks were observed in HCs and pwMS(BZDn), highlighting a consistent, paradigm-independent mechanism.

Taken together, these findings demonstrate that the aperiodic 1/f slope is a sensitive, paradigm-independent marker of cognitive control and E/I balance. Reduced modulation in response to distractors among pwMS(BZDp) highlights benzodiazepine-related disruptions in inhibitory neural processes underlying cognitive deficits. These findings underscore the value of aperiodic spectral measures to deepen understanding and potentially guide therapeutic interventions targeting cognitive impairments in MS.

Highlights

• The 1/f slope was significantly modulated during an auditory oddball task across all stimulus types in healthy controls and people with multiple sclerosis (pwMS).

• This modulation was more pronounced for non-standard stimuli (distractor and target) than for standard stimuli.

• Healthy controls showed a larger 1/f slope modulation (suggesting more inhibition) following distractor trials compared to target trials while, this pattern was reversed in pwMS.

• This modulation significantly correlated with visuospatial memory, as measured by the BVMT-R, in pwMS not treated with benzodiazepines.

• We further correlated the 1/f slope modulation during the auditory oddball task with the 1/f slope modulation previously described during a working memory task and observed strong correlations (r=0.4-0.6, p<0.001) across paradigms.